PROJECT SUMMARY/ABSTRACT Alzheimer?s disease (AD) is a devastating neurodegenerative disorder that is characterized by progressive cognitive and functional impairment, and ultimately memory loss. Most cases of AD are late-onset and sporadic, with no evidence for a Mendelian pattern of inheritance, suggesting a significant role for environmental contributions to disease onset and/or progression. There are no validated treatments that slow, halt or reverse the symptoms of AD, and currently approved pharmacotherapies provide only modest and transient benefits. Further, many recent drug trials have failed to meet their endpoints of dissolving hallmark plaques in the AD brain or improving memory. The pathological consequences leading to AD are believed to involve accumulation of the amyloid-? peptide (A?) in neurons followed by the deposition of neurofibrillary tangles, which result in the onset of synaptic and neuronal dysfunction and neuronal death in specific brain regions. AD pathology is characterized by an inflammatory response in circulating immune cells and in the brain's resident immune cells, known as microglia. Intriguingly, it has recently been shown that the microbiome of AD patients differs from that of matched healthy controls, and that antibiotic treatment in mouse models impacts A? pathology and immune responses. Notably, the microbiome regulates numerous immune cell types throughout the body. Our laboratory has discovered specific bacterial molecules that prevent inflammation, identified receptors and signaling pathways in immune cells that mediate anti-inflammatory effects, and revealed how host-microbial interactions can ameliorate inflammatory conditions in several mouse models. These major advances have been funded by the parent R01 from NIDDK. This Administrative Supplement proposes to leverage our ground-breaking studies of specific gut microbial molecules with potent anti- inflammatory properties to test novel treatments for AD. Specific Aim 1 will profile the mucosal immune response, in unprecedented detail, in two well-established mouse models of AD. Further, we will determine if experimental gut inflammation accelerates or exacerbates AD-like pathologies and symptoms in mice. Specific aim 2 will focus on testing novel therapies for AD by suppressing inflammation with gut bacterial molecules that prevent and treat intestinal inflammation. The innovative hypothesis being tested is that mucosal inflammation contributes to AD-like pathologies and behaviors in mouse models, and activation of anti-inflammatory immune cells by gut bacteria ameliorates learning and memory deficits. Validation of this concept, and discovery of underling mechanisms of action, will de-risk further research into the gut-brain connection in AD, and advance the exciting possibility that harnessing the gut microbiome may lead to safe and effective therapeutic options for Alzheimer?s disease, one of the greatest medical concerns of current and future generations.